Very Elderly Patients with Myeloproliferative Neoplasms: Phenotypic Distinctions and Prognostic Determinants of Complications and Mortality

Abstract Background and methods: Increasing life expectancy has had the impact of increasing the proportion of patients with myeloproliferative neoplasms (MPN) aged ≥75 years (very elderly patients; VEP). However, few studies have evaluated the phenotype and prognostic factors specific to this population. This is a retrospective multicenter chart review (11 Quebec centers) of VEP with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) diagnosed between 1978 and 2019, enrolled in the CML-MPN Quebec Research Group registry. All diagnoses were made according to World Health Organization 2016 criteria (Blood. 2016;127:2391), with exemption of bone marrow biopsies in select patients. Standard statistical methods were used for all analyses. Results: Of the 753 patients studied in the registry, 114 patients (15%) were ≥75 years old (VEP) (Table 1). These subjects had a median age of 79 years (range 75-95) with incidence of PV, ET and MF of 38%, 51% and 11% respectively. Compared to patients <75 years old, VEP were less likely to be male (35% vs 45%, p = 0.05), had more frequent and higher levels of leukocytosis (11.4 vs 9.7 x 10 9 / L, p <0.0001), were more frequently "triple negative" and less commonly CALR-mutated (p = 0.0005), and presented significantly higher allelic burdens (45% vs 36%, p = 0.03). VEP also had more cardiovascular comorbidities (p <0.0001) and were more often classified as "high risk" (86% vs. 43%, <0.0001). A history of arterial thrombosis prior to/at diagnosis was more common in VEP vs younger patients (14% vs 7.2%, p = 0.02), as was a global history of arterial and/or venous thrombosis at any time during the follow up (25% vs 18%, p = 0.05). Sites of venous events were specifically skewed towards lower extremity deep vein thrombosis in VEP (75%) vs variously distributed in younger patients (p = 0.05). Bleeding rates were similar among the two groups (16% VEP and 17% non-VEP, p = 0.7) while fewer fibrotic (3% vs 8%, p = 0.03) and leukemic transformations (0 vs 2%, p = 0.04) were recorded in VEP. Significantly fewer bone marrow biopsies were performed in VEP (41% versus 54%, p = 0.01). This cohort was, however, more likely to receive cytoreductive therapy (76% vs 67%, p = 0.05), predominantly hydroxyurea (70% vs 59%, p = 0.02). Multivariate analysis revealed the presence of splenomegaly (HR 4.5; 1.2-17.1, p = 0.03) and smoking status (active/former vs never smokers) (HR 5.2; 1.1-24.9, p = 0.03) as predictors of shortened overall survival for the VEP population (Table 2). It also disclosed higher leukocyte count (p = 0.005) and the presence of diabetes mellitus (p = 0.05) as significant risk factors for shortened hemorrhage-free survival. Platelet count (p = 0.03) and smoking status (p = 0.02) were found to be significant determinants of thrombosis-free survival in univariate analysis but did not maintain their significance in multivariate testing. Kaplan-Meier survival data examining age-stratified outcomes in VEP vs younger patients revealed significantly shorter overall survival in VEP (14.2 years vs not reached, p < 0.0001) (Figure 1). The VEP cohort also displayed significantly reduced arterial thrombosis-free survival (incidence of 6.1% vs 3.9%, p = 0.01). There was no significant difference in event data for venous thrombosis-free (4% in both, p = 0.2) and myelofibrosis-free (2.6% versus 7.8%, p = 0.6) survival. Conclusion: This data addressing VEP with MPN exposes, for the first time: i) a characteristic phenotype (predominantly female, higher leukocyte counts, higher allele burden), ii) distinct adverse outcome patterns, particularly with regard to arterial thrombosis, and iii) unique and independent prognostic factors for survival, suggesting that VEP with MPN constitute a biologically, phenotypically, and prognostically distinct population. Figure 1 Figure 1. Disclosures Busque: Novartis: Consultancy. Szuber: Novartis: Honoraria.

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Risk Factors for Thrombosis Among 1,545 Patients with Polycythemia Vera: An International Study.

Blood ◽

10.1182/blood.v120.21.2849.2849 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2849-2849

Author(s):

Guido Finazzi ◽

Elisa Rumi ◽

Alessandro M. Vannucchi ◽

Maria Luigia Randi ◽

Ilaria Nichele ◽

...

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Board Of Directors ◽

Arterial Thrombosis ◽

Myeloproliferative Neoplasms ◽

Univariate Analysis ◽

Abnormal Karyotype ◽

Advisory Committees ◽

Free Survival ◽

History Of

Abstract Abstract 2849 Background We have previously reported on the natural history of polycythemia vera (PV), focusing primarily on overall and leukemia-free survival (ASH Annual Meeting Abstracts. 2011;118(21):277-). In the current study, we present, on behalf of the International Working Group for Myeloproliferative neoplasms Resarch and Treatment (IWG-MRT), our analysis regarding risk factors for thrombosis. Methods Under the auspices of IWG-MRT, seven international centers of excellence for myeloproliferative neoplasms participated in the current study. The two principle investigators (AT and TB) reviewed all the cases and selected 1,545 patients who met the 2008 WHO criteria for PV, were age 18 years or older, diagnosed after 1970, and whose submitted data included diagnostically essential information. Results I: Presenting Features Median age was 61 years (range, 18–95; 51% females). Arterial and venous thrombosis history before or at diagnosis was documented in 246 (16%) patients and 114 (7.4%) patients, respectively. Major hemorrhage hemorrhage before or at diagnosis was documented in 17 (4.5%) patients. Other features at diagnosis included pruritus (36%), microvascular disturbances (28.5%), palpable splenomegaly (36%), abnormal karyotype (12%), leukoerythroblastosis (6%), increased LDH (50%), thrombocytosis (53%), extreme thrombocytosis (platelets >1 million mm3; 4%) leukocytosis (49%), JAK2 V617F (95%), other JAK2 mutations (3%), subnormal serum erythropoietin (Epo) level (81%), and endogenous erythroid colonies (EEC; 73%). History of hypertension (46%), hyperlipidemia (18.3%), diabetes (8.4%), and tobacco use (16%) was also obtained. Results II: Clinical Course To date, 347 (23%) deaths, 50 (3%) leukemic progressions, and 138 (9%) fibrotic transformations have been recorded. Overall, cytoreductive treatment was not used in 416 (27%) patients and the remaining were exposed to different agents based on physician discretion. Post-diagnosis arterial or venous thrombosis occurred in 184 (12%) and 137 (9%) patients, respectively. Results III: Risk Factors for thrombosis Arterial and venous thrombosis-free survival, from time of diagnosis, were separately analyzed using the occurrence of thrombosis as the endpoint (uncensored variable) and last follow-up or death before thrombosis as the censored variable. In univariate analysis, the following were significantly associated with post-diagnosis arterial thrombosis: advanced age, leukocyte count, presence of a leukoerythroblastic smear (LES), history of hypertension and history of arterial thrombosis before or at diagnosis; multivariable analysis using all these five parameters identified arterial thrombosis history (RR 2.5, 95% CI 1.6–4.0; p<0.0001), LES (RR 2.3, 95% CI 1.3–4.2; p=0.005) and history of hypertension (RR 1.6, 95% CI 1.1–2.4; p=0.02) as independent predictors of post-diagnosis arterial thrombosis. Only two parameters predicted post-diagnosis venous thrombosis, in univariate analysis, and both remained significant during multivariable analysis: abnormal karyotype (RR 3.1, 95% CI 1.7–5.4; p=0.0001) and history of venous thrombosis (RR 2.4, 95% CI 1.2–4.9). Of note, the type of JAK2 mutation or presence of either subnormal Epo or EEC did not influence either arterial or venous thrombosis. Results IV: Risk Stratification for arterial and venous thrombosis The figures below illustrated arterial or venous thrombosis-free survival of patients stratified by the absence of all risk factors or presence of one or ≥2 risk factors. For arterial thrombosis, the presence of ≥2 risk factors clearly delineated a high risk group (RR 3.1, 95% CI 1.9–5.0) whereas the presence of one (RR 2.4, 95% CI 1.4–4.2) or two risk factors (RR 10.1, 95% CI 3.6–28.2) for venous thrombosis delineated an intermediate and high risk group, respectively. Conclusions: History of arterial thrombosis and venous thrombosis are key risk factors, respectively, for recurrent arterial and venous thrombosis in PV. In addition, abnormal karyotype is a strong independent risk factor for venous thrombosis and the presence of leukoerythroblastosis and hypertension, for arterial thrombosis. This information allows for a simple and practical risk stratification and raises interesting pathogenetic implications that require further clarification. Disclosures: Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees. Gisslinger:Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Clonal Evolution As Determined By Sequential Bone Marrow Karyotype Analysis During JAK Inhibitor Therapy For Myelofibrosis: Impact On Treatment Response and Overall and Leukemia-Free Survival

Blood ◽

10.1182/blood.v122.21.2821.2821 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2821-2821 ◽

Cited By ~ 1

Author(s):

Ramy A. Abdelrahman ◽

Kebede Begna ◽

Darci Zblewski ◽

Aref Al-Kali ◽

Mrinal M. Patnaik ◽

...

Keyword(s):

Clinical Trial ◽

Bone Marrow ◽

Overall Survival ◽

Clonal Evolution ◽

Univariate Analysis ◽

Support Service ◽

Risk Category ◽

Leukemic Transformation ◽

Bone Marrow Biopsies ◽

Free Survival

Abstract Background While unfavorable karyotype at referral is associated with significantly inferior overall and leukemia-free survival in myelofibrosis (MF) patients (Blood. 2011 Oct 27;118(17):4595), the incidence of clonal evolution during JAK inhibitor (JAKi) treatment and its clinical significance are not currently known. We conducted a sponsor-independent, single-center retrospective analysis examining the phenotypic correlates and prognostic impact of clonal evolution during JAKi treatment. Methods Clinical, cytogenetic and molecular data were collected on MF patients treated with one or more JAKi on a clinical trial at the Mayo Clinic, Rochester, MN. Baseline data pertained to the onset of treatment with first JAKi. Karyotype risk categories were as previously defined (Blood. 2011 Oct 27;118(17):4595). Serial bone marrow biopsies were obtained at varying frequencies based on individual JAKi protocol requirements. Mutation screening was performed as previously described (Leukemia. 2013 Apr 26. doi: 10.1038/leu.2013.119). Information on survival and leukemic transformation was updated in July 2013. Results A total of 157 MF patients were studied (60% male; median age 65 years, range 34-89 years). The DIPSS-plus distribution was: Low/Int-1 20 (13%), Int-2 66 (42%), and High 71 (45%). The first JAKi was momelotinib (CYT387) in 79 patients (50%), ruxolitinib in 51 (33%) and fedratinib (SAR302503) in 27 (17%). Median follow up from first JAKi treatment was 30 months (range 1-67 months); during this period, 72 deaths (46%) and 14 (9%) leukemic transformations were documented. Eighty nine patients (57%) had a median total 3 (range 2-8) bone marrow biopsies with karyotype analysis during JAKi treatment. Of these, 21 patients (24%) showed clonal evolution (ie, acquisition or loss of one or more chromosome abnormalities when comparing last observed karyotype during JAKi treatment to baseline). Overall, 13 patients (15%) had upstaging of karyotype risk category (eg, normal to unfavorable), 9 (10%) had downstaging (eg, favorable to normal) and 67 (75%) had no change. Acquisition of worse-than-baseline karyotype was significantly higher in DIPSS-plus high-risk patients (26%) versus non-high risk patients (6%) (p=0.03). There was no association between acquisition of a worse karyotype category and baseline karyotype risk category or ASXL1 or SRSF2 mutation status. There was borderline association with RBC transfusion-dependence and constitutional symptoms at baseline (p=0.06). There was no relationship between clonal evolution and achievement of spleen or anemia response during JAKi treatment (p>0.05). The median overall survival of the entire cohort was 41 months. On univariate analysis, overall survival was significantly worse in patients who acquired a worse-than-baseline karyotype risk category during JAKi treatment (n=13, 77% deaths, median survival=31 months) versus those who did not (n=76, 43% deaths, median survival=52 months) (p=0.01) (Figure). On multivariate analysis, the prognostic significance of acquiring a worse karyotype risk category was maintained against all individual DIPSS-plus prognostic variables, including baseline karyotype risk category, except age >65 years. On univariate analysis, leukemia-free survival was significantly worse in patients who acquired a worse-than-baseline karyotype risk category during JAKi treatment (n=13, 31% leukemic transformation, median leukemia-free survival=32 months) versus those who did not (n=76, 8% leukemic transformation, median leukemia-free survival not reached) (p=0.0006) (Figure). On multivariate analysis against known predictors of leukemic risk in PMF patients (ie, baseline unfavorable karyotype, SRSF1 mutated status and platelet count <100 x 109/L), only acquisition of a worse-than-baseline karyotype risk category maintained its prognostic value (HR 5.3, p=0.03) Conclusions This is the first study to examine the incidence of clonal evolution during JAKi treatment in MF patients. Approximately 25% of patients exhibited clonal evolution; acquisition of a worse-than-baseline karyotype risk category had a strong and independent association with inferior leukemia-free survival. A similar association was also observed for inferior overall survival, albeit not independent of older age. In contrast, there was no association with spleen or anemia response during JAKi treatment. Disclosures: Pardanani: Bristol Myers Squibb: Clinical trial support Other; Sanofi: Clinical trial support. Publication support service., Clinical trial support. Publication support service. Other; PharmaMar: Clinical trial support, Clinical trial support Other; JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other.

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Patterns of Care of Diffuse Large B Cell Lymphoma Patients 80 Years and Older: Worse Outcomes after Treatment without Increased Relapse

Blood ◽

10.1182/blood-2018-99-117587 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 575-575 ◽

Cited By ~ 1

Author(s):

Madison Keenan ◽

Kirsten Marie Boughan ◽

Brenda Cooper ◽

Molly M Gallogly ◽

Stanton L. Gerson ◽

...

Keyword(s):

Overall Survival ◽

Cumulative Incidence ◽

Statistical Difference ◽

Progression Free Survival ◽

Advisory Board ◽

Competing Risk ◽

Disease Relapse ◽

Very Elderly ◽

Free Survival ◽

Younger Patients

Abstract Introduction: Very advanced age (≥80 years) DLBCL patients have worse prognosis. These unfavorable outcomes are largely considered to be a result of the combined effects of increased comorbidities, frailty, diminished tolerance and access to effective chemoimmunotherapy. It is not clear yet whether DLBCL patients of very advanced age have disease that is intrinsically more aggressive. Methods: We accessed the Stem Cell Transplant and Hematologic Malignancies database of University Hospitals Seidman Cancer Center for DLBCL patients diagnosed between 2000 and 2016. Information collected included demographic characteristics, baseline laboratory and disease information, as well as treatment details. Progression free survival and overall survival were calculated from time of diagnosis using Kaplan Meier methodology, comparisons were done with log rank. Cumulative incidence of relapse with death as competing risk was calculated for patients who underwent treatment, comparisons between age groups were done with the Gray test. Results: A total of 542 DLBCL patients were identified, 85 (16%) were older than 80 years. Table 1 shows the baseline demographic and disease characteristics. Older patients had a higher incidence of comorbidities, specifically cardiovascular comorbidities, prior renal insufficiency, and hyperlipidemia. Expectedly, very elderly patients had higher R-IPI, with a trend towards worse performance status that did not reach statistical difference. The proportion of patients diagnosed with non - germinal center DLBCL was not different than younger DLBCL patients, and there was no statistical difference in the incidence of double expressor or double hit lymphomas, possibly secondary to the small number of patients tested. A smaller proportion of patients ≥ 80 years received antineoplastic therapy (89% vs. 98%, p = 0.001), and use of less intense therapy was more common (table 2). Sixty one percent of patients, however, were still treated with R-CHOP (38.8%) or R-miniCHOP (22.2%). The overall response rate (ORR) for any therapy was 68.2%, lower than the ORR for younger patients (85.9%, p = 0.007). When only patients treated with RCHOP/R-miniCHOP were included, the difference in ORR was smaller, though still statistically significant (77.5% vs. 89.8%, p = 0.021). Median number of cycles was similar (5 vs. 6 cycles, respectively). Patients of all ages treated with single agent rituximab presented an ORR of 43%. After a median of 40 months follow up, estimated 4-year overall survival was 42% (95% CI 31-54%) for patients ≥ 80 years, 67% for patients aged between 60 and 79 years (95% CI 61-74%) and 78% for patients < 60 years (95% CI 73-84%) (Figure 1). Four - year survival for patients ≥80 years treated with R-CHOP or R-miniCHOP chemoimmunotherapy was 50% (95% CI 36-65%) vs. 75% for younger patients (95% CI 70-79%) (p<0.001), with 4-year PFS of 48% vs. 63% (95% CI 58-68%) (p = 0.04). Cumulative incidence of relapse (with death in remission as competing risk) for chemoimmunotherapy - treated patients at 1 and 4 years was 10% (95% CI 4-22%) and 20% (95% CI 11-37%), respectively for patients older than 80 years and 20% (95% CI 11-36%) and 29% (95% CI 25-35%), respectively for younger patients (p = 0.12) (Figure 2). There was no observed difference in the rates of disease - related mortality (53% vs. 61%, p = 0.5). Conclusions: Very elderly (≥80 years of age) DLBCL patients have significantly worse overall survival, progression free survival, and treatment response rates than younger patients. However, when chemoimmunotherapy is feasible, disease relapse rates are comparable to those of younger patients, and increased mortality does not appear to be a result of increased disease relapse. Additional research is needed to establish more widely applicable, better tolerated effective treatment regimens for this patient population. Disclosures Lazarus: Pluristem Ltd.: Consultancy. Malek:Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Tomlinson:Foundation Medicine: Consultancy. Caimi:Genentech: Other: Advisory Board PArticipation, Research Funding; Kite Pharma: Other: Advisory Board Participation; Celgene: Speakers Bureau; Kite Pharma: Other: Advisory Board Participation.

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IMMU-08. MODELING UPFRONT GLIOBLASTOMA SURGICAL RESECTION AND STEROID USE REVEALS IMMUNOSUPPRESSIVE CHANGES AND SUGGESTS THAT PERIPHERAL LYMPHOCYTE COUNTS ARE ASSOCIATED WITH TUMOR VOLUME AND PROGNOSIS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.439 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii106-ii106

Author(s):

Balint Otvos ◽

Tyler Alban ◽

Matthew Grabowski ◽

Defne Bayik ◽

Robert Winkelman ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Surgical Resection ◽

Cd8 T Cells ◽

Tumor Volume ◽

Progression Free Survival ◽

Peripheral Lymphocyte ◽

Steroid Use ◽

Free Survival ◽

Steroid Administration

Abstract Glioblastoma (GBM) and its treatment produces systemic immunosuppression, which is being targeted by immunotherapies. However, it remains unclear how surgical resection and steroids specifically in GBM alter the immune system. To further explore this issue, immunocompetent C57Bl/6 mice were intracranially inoculated with syngeneic glioma cells (GL261 and CT-2A) and growth of tumors was evaluated by MRI. Host immune cell populations were analyzed during surgical resection and steroid administration. Mice with surgically resected tumors had a longer median survival compared to mice subjected to tumor biopsies, and had increased bone marrow sequestration of both CD4 and CD8 T cells with corresponding decreased blood lymphocytes. Furthermore, physiologic doses of dexamethasone administered perioperatively decreased tumor edema, but increased the number and proliferative capacity of both marrow and circulating MDSCs while generating no survival benefit. Independent of therapy or dexamethasone, intracranial tumor volume correlated linearly with decreased CD4 and CD8 T cells in peripheral blood, and increased T cell sequestration within the bone marrow. We validated these parameters in steroid-naïve newly diagnosed GBM patients and observed decreased lymphocytes correlated linearly with increased tumor volume. When initial lymphocyte counts in both steroid-naïve and steroid-administered patients were used in univariate and multivariate models predicting progression-free survival and overall survival, decreased initial lymphocyte counts were an independent predictor of decreased progression free survival and decreased overall survival, with steroid use and initial tumor size falling out of significance during stepwise selection. Taken together, tumor volume is linearly correlated with marrow sequestration of lymphoid cells, but both surgery and steroid administration further suppress active immune responses along lymphoid and myeloid lineages. Furthermore, decreasing peripheral lymphocyte counts at diagnosis of GBM indicate an immune system less able to mount responses to the tumor and portent a worse progression free and overall survival.

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Increased expression of cyclin-D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

American Journal of Hematology ◽

10.1002/ajh.23223 ◽

2012 ◽

Vol 87 (7) ◽

pp. 734-736 ◽

Cited By ~ 5

Author(s):

Anna Tasidou ◽

Maria Roussou ◽

Evangelos Terpos ◽

Efstathios Kastritis ◽

Maria Gkotzamanidou ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Cyclin D1 ◽

Novel Agents ◽

Bone Marrow Biopsies

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Diffuse osteosclerosis in hairy cell leukemia

Blood ◽

10.1182/blood.v74.6.2066.2066 ◽

1989 ◽

Vol 74 (6) ◽

pp. 2066-2069 ◽

Cited By ~ 17

Author(s):

LA VanderMolen ◽

WJ Urba ◽

DL Longo ◽

J Lawrence ◽

H Gralnick ◽

...

Keyword(s):

Bone Marrow ◽

Interferon Alpha ◽

Successful Treatment ◽

Hairy Cell Leukemia ◽

Malignant Disease ◽

Hairy Cell ◽

Cell Leukemia ◽

Bone Marrow Biopsies ◽

Biopsy Needle ◽

History Of

Abstract We describe two patients with a new clinical pathologic syndrome of diffuse osteosclerosis in association with hairy cell leukemia. In both patients bone marrow biopsies could not be obtained due to extremely hard bones and inability to insert the biopsy needle; neither patient had a history of bony pain or fracture. The osteosclerotic process in one patient stabilized after successful treatment of her hairy cell leukemia with interferon alpha and deoxycoformycin suggesting that the osteosclerosis observed was related to the underlying malignant disease. Possible etiologic mechanisms are discussed.

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Tissue microarray technique is applicable to bone marrow biopsies of myeloproliferative neoplasms

Histochemistry and Cell Biology ◽

10.1007/s00418-016-1476-x ◽

2016 ◽

Vol 147 (1) ◽

pp. 75-82 ◽

Cited By ~ 4

Author(s):

Kathrin A. Limberger ◽

Lioudmila Bogatyreva ◽

Rumyana Todorova ◽

Bettina Herde ◽

Dieter Hauschke ◽

...

Keyword(s):

Bone Marrow ◽

Tissue Microarray ◽

Myeloproliferative Neoplasms ◽

Bone Marrow Biopsies ◽

Microarray Technique

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EPID-07. HEMATOLOGICAL ADVERSE EVENTS IN GLIOBLASTOMA PATIENTS TREATED WITH TEMOZOLOMIDE

Neuro-Oncology ◽

10.1093/neuonc/noz175.307 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi75-vi76

Author(s):

Catherine Garcia ◽

Zin Myint ◽

Rani Jayswal ◽

Allison Butts ◽

Heidi Weiss ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Protective Factor ◽

Significant Proportion ◽

Progression Free Survival ◽

Free Survival ◽

Significant Difference ◽

History Of ◽

Grade 3 ◽

Severe Grade

Abstract BACKGROUND Temozolomide (TMZ) is the cornerstone for glioblastoma (GBM) treatment. A significant proportion of patients develops hematologic toxicities with limited investigations on outcomes and risk factors for their development. METHODS Our study combines data from the two largest group trials, RTOG 0525 and RTOG 0825, to analyze serious hematologic adverse events (HAE) associated with TMZ therapy for GBM. We analyzed frequency and outcomes of HAE during chemoradiation. RESULTS 1154 patients were evaluated with a median age of 57 years. Over 79% of patients developed HAE during the entire course of GBM treatment. During chemoradiation the most common HAE during chemoradiation was lymphopenia (41.5%), followed by thrombocytopenia (39.0%), and anemia (35.3%). Of these, 34.1% were severe (Grade 3 or 4) and 65.9% were mild (grade 1 or 2). During maintenance the most common HAE was leukopenia (50.7%), followed by neutropenia (50.4%), and lymphopenia (45.3%). MGMT methylation was not associated with HAEs. A history of HAEs during chemoradiation was a protective factor for developing HAEs during maintenance. MGMT methylated and age younger than 50 were protective factors for mortality. Patients that presented HAEs anytime during treatment had a longer overall survival and progression free survival. There was no significant difference in survival between mild or severe HAEs. CONCLUSION HAE are common during chemoradiation with TMZ for GBM, but are more commonly grade 1 or 2 per CTCAE. HAE during GBM treatment is associated with decreased progression free survival and overall survival.

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Clinical Relevance of Bone Marrow Fibrosis and CD34-Positive Cell Clusters in Primary Myelodysplastic Syndromes

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.2246 ◽

2009 ◽

Vol 27 (5) ◽

pp. 754-762 ◽

Cited By ~ 148

Author(s):

Matteo Giovanni Della Porta ◽

Luca Malcovati ◽

Emanuela Boveri ◽

Erica Travaglino ◽

Daniela Pietra ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Myelodysplastic Syndromes ◽

Scoring System ◽

Transfusion Requirement ◽

Free Survival ◽

Cell Clusters ◽

Multilineage Dysplasia ◽

Poor Risk ◽

Marrow Fibrosis

Purpose We studied bone marrow (BM) histologic abnormalities in myelodysplastic syndromes (MDS) classified according to WHO criteria to determine their clinical correlates and prognostic value. Patients and Methods Three hundred one consecutive patients were retrospectively evaluated for BM fibrosis and CD34 immunoreactivity. Marrow fibrosis was assessed following the European consensus guidelines. Results Moderate to severe BM fibrosis was detected in 17% of cases and was associated with multilineage dysplasia (P = .001), high transfusion requirement (P < .001), and poor-risk cytogenetics (P = .007). CD34+ cell clusters were found in 23% of patients and were associated with WHO categories with excess of blasts (P < .001) and poor-risk cytogenetics (P = .001). In multivariable analysis, BM fibrosis and presence of CD34+ cell clusters had independent negative impact on overall survival (P < .001 and P = .019, respectively) and leukemia-free survival (P < .001 and P = .004, respectively). A hierarchical clustering analysis identified three subsets of patients with distinct clinical features. One cluster consisted mainly of patients with BM fibrosis, multilineage dysplasia, and high transfusion requirement; these individuals had lower overall survival and leukemia-free survival (P = .001 and P < .001, respectively). Within patients stratified according to International Prognostic Scoring System and WHO classification–based Prognostic Scoring System categories, BM fibrosis involved a shift to a one-step more advanced risk group. Conclusion BM fibrosis identifies a distinct subgroup of MDS with multilineage dysplasia, high transfusion requirement, and poor prognosis and represents an independent prognostic factor that may be useful in clinical decision making. Furthermore, the presence of CD34+ cell clusters is an independent risk factor for progression to acute leukemia.

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Expression of Phosphorylated Signal Transducer and Activator of Transcription 5 (pSTAT5) Is Associated with An Increased Risk of Death In Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v116.21.1675.1675 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1675-1675

Author(s):

Anna Brady ◽

Sarah Gibson ◽

Lisa Rybicki ◽

Eric Hsi ◽

Edward Copelan ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Prognostic Factors ◽

Myeloid Leukemia ◽

Signal Transducer ◽

Newly Diagnosed ◽

Risk Of Death ◽

Increased Risk ◽

History Of ◽

Acute Myeloid

Abstract Abstract 1675 Background: Acute myeloid leukemia (AML) is characterized by rapid growth, resistance to therapy, and poor overall survival. Clinical and biologic prognostic markers can help define pathogenesis, guide treatment, and identify novel therapies. Phosphorylated signal transducer and activator of transcription 5 (pSTAT5) is one such potential marker. The transcription factor STAT5 regulates many aspects of cell growth, survival, and differentiation. Constitutive activation of STAT5 (by phosphorylation) has been identified in a number of malignancies, including AML. We investigated whether the level of pSTAT5 expression correlates with complete remission (CR) rates, progression-free survival (PFS), and overall survival (OS) in patients (pts) with newly diagnosed AML. Methods: From 1999 to 2005, all adult pts with newly diagnosed AML (WHO criteria) receiving induction chemotherapy and with an available diagnostic bone marrow biopsy performed at our institution were evaluated. B5-fixed bone marrow core biopsies were reviewed for areas with the highest concentration of blasts. A tissue microarray was constructed using 1 mm cores. The cores were arrayed in duplicate in the majority of samples. Immunohistochemistry was performed for pSTAT5 with anti-pSTAT5 a/b Y695/99 mouse monoclonal antibody (AX1; Advantex Bioreagents) using automated stainers and heat-induced epitope retrieval. In each case, five hundred blasts were counted. The percentage of cells staining positive for pSTAT5 expression was determined by a pathologist blinded to clinical results. Standard metaphase karyotypes were classified into cytogenetic (CG) risk groups by CALGB criteria. Cox proportional hazards analysis was used to identify univariate and multivariate prognostic factors for CR, PFS, and OS, including age at diagnosis, history of an antecedent hematologic disorder (AHD), WBC at diagnosis, pSTAT5 expression, and CG risk group. Results: Adequate tissue and clinical data were available in 112 pts. The median age was 57 years, and median WBC at diagnosis 12.0 K/ μL. Twenty six percent of pts had favorable CG, 41% intermediate risk, 27% high risk, and 6% other (unknown or could not be classified). Nineteen percent of pts had an AHD. pSTAT5 expression was absent in 58% of pts. The remainder of the pts had: 1–5% pSTAT5 (25% of pts), 10% pSTAT5 (11% of pts), 20% pSTAT5 (4% of pts), 30% pSTAT5 (1% of pts), and 50% pSTAT5 (2% of pts). Seventy percent of all pts achieved a CR following induction chemotherapy. Sixty-four percent of pts received post-remission chemotherapy, 3.6% an autologous transplant, and 13.6% an allogeneic transplant in first CR. Median PFS and OS were 9.6 months and 16.0 months, respectively. On univariate analysis, age, history of AHD, WBC at diagnosis, CG risk, and any pSTAT5 expression were prognostic factors for PFS and OS. In multivariable analyses controlling for the above prognostic factors, pSTAT5 expression > 0 was also significantly associated with an increased risk of death (HR 1.96, 95% CI 1.19–3.23, p=0.008), progression or death (HR 1.64, 95% CI 1.01–2.66, p=0.046), and relapse after achieving CR (HR 2.31, 95% CI 1.16–4.63, p=0.018). pSTAT5 expression was not a predictor of achievement of CR. Conclusions: pSTAT5 expression in newly diagnosed adults with AML is associated with a decreased PFS, decreased OS, and increased risk of relapse. Validation of its prognostic value requires additional study. Agents targeting this signaling pathway might improve the outcome of pts with AML. Disclosures: No relevant conflicts of interest to declare.

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